Research Article: Panx1 and P2X7R are associated with impaired skeletal health and delayed bone development in early onset of type 1 diabetes
Abstract:
Type 1 diabetes (T1D) is a chronic autoimmune endocrine disorder that disrupts multiple physiological systems beyond glucose homeostasis. An underrecognized complication is impaired skeletal development during childhood and adolescence, a critical period for bone accrual. This study aimed to define the early-life effects of T1D on load-induced bone adaptation and to investigate the role of the osteocyte Panx1-P2X7R mechanosignaling complex in diabetes-associated skeletal deficits.
Akita (C57BL/6J-Ins2 Akita ) and age-matched wild-type mice were subjected to treadmill loading (1, 2, or 4 weeks; 5 days/week, 300 m/day) or maintained under normal cage activity. Femoral bone density and anabolic responses were assessed using in vivo imaging and dynamic histomorphometry. In parallel, osteocytes cultured under normal or high-glucose (HG) conditions were exposed to oscillatory fluid shear stress (OFSS; 1, 3, or 5 days) to model mechanical loading in vitro . Temporal changes in Panx1-P2X7R signaling components and inflammatory mediators in bone tissue and cultured osteocytes were analyzed by Western blot and quantitative PCR.
Load-induced periosteal bone formation in wild-type mice was accompanied by adaptive regulation of Panx1-P2X7R expression, whereas this response was disrupted in young adult T1D mice. Dysregulation emerged after one week of loading and was recapitulated in osteocytes exposed to OFSS in vitro under high glucose conditions. Diabetic bone and HG-conditioned osteocytes exhibited sustained inflammatory activation, including upregulation of the NLRP3 inflammasome and proinflammatory cytokines (IL-1?, TNF-?). The failure of Panx1-P2X7R to adapt to mechanical loading, together with persistent inflammation, suggests a mechanistic link between impaired mechanotransduction and inflammasome activation in T1D.
Early-onset T1D impairs bone mechanoadaptation and is associated with dysregulated Panx1-P2X7R signaling and heightened inflammatory responses. Given the established roles of Panx1 and P2X7R in mechanosensitive signaling and inflammation, their disruption likely contributes to defective skeletal adaptation and inflammatory bone pathology, ultimately increasing skeletal fragility in T1D.
Introduction:
Bone loss in people with type 1 diabetes (T1D) is a diabetic complication that is often overlooked. Studies have shown that T1D children and adults exhibit low bone mineral density (BMD), along with a reduction in bone mass ranging from 5% to over 21% ( 1 – 4 ). Given that T1D typically manifests early in adolescence, insufficient accrual of peak bone mass and impaired bone formation are likely to significantly contribute to compromising the skeletal integrity of individuals with T1D. Childhood and adolescence…
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